Renin (EC 3.4.99.19) is an aspartyl protease found in the kidney which, on release into the blood, cleaves circulating angiotensinogen to yield the decapeptide angiotensin I. This is cleaved by kininase II to yield angiotensin II. This hormone has multiple activities including elevation of blood pressure, aldosterone release, direct conservation of sodium by the kidney, and neurotropic effects. Angiotensin is responsible for the elevated blood pressures observed in renovascular hypertension and has been implicated in the etiology of other forms of hypertension also. Previous research from this laboratory involved the design and chemical synthesis of angiotensionogen analogs which are competitive inhibitors of renin. The most effective inhibitor, Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys, is both effective in vitro (Ki equals 2 micromoles) and in vivo. In the salt depleted monkey, mean arterial pressure is lowered about 35 mm. Hg. Research proposed in this application involves modification of the inhibitor to increase in vivo half life into at least 30 minutes. This will be done by attaching the decapeptide to soluble dextran which is cleared more slowly from circulation than the small inhibitor. In addition, modifications to increase resistance of the renin inhibitors to proteolytic enzymes in vivo are proposed. Methods for measuring the rate and location of enzymatic degradation of the peptide are discussed as well.